This invention relates to novel derivatives of minocycline and doxycline, pharmaceutical compositions containing same and their use in lowering IgE levels in mammals, especially humans, suffering from a disease where IgE is pathogenic, such as allergies, asthma, especially human allergic response, and diseases associated with an inflammatory response.
Diseases involving inflammation are characterized by the influx of certain cell types and mediators, the presence of which can lead to tissue damage and sometimes death. Diseases involving inflammation are particularly harmful when they afflict the respiratory system, resulting in obstructed breathing, hypoxemia, hypercapnia and lung tissue damage. Obstructive diseases of the airways are characterized by air flow limitation (i.e., airflow obstruction or narrowing) due to constriction of airway smooth muscle, edema and hypersecretion of mucous leading to increased work in breathing, dyspnea, hypoxemia and hypercapnia.
A variety of inflammatory agents can provide air flow limitation, such as for example, allergens. In particular, allergens and other agents in allergic or sensitized animals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymphocytes, eosinophils, mast cells, basophils, neutrophils, macrophages, monocytes, fibroblasts and platelets. A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness. Thus, a common consequence of inflammation is airflow limitation and/or airway hyperresponsiveness.
Asthma is a significant disease of the lung which is typically characterized by periodic air flow limitation and/or hyperresponsiveness to various stimuli which results in excessive airways narrowing. Other characteristics can include inflammation of airways and eosinophila. More particularly, allergic asthma is often characterized by eosinophilic airway inflammation and airway responsiveness.
An estimated 16 million persons in the U.S. have asthma, which is about 10% of the population. The numbers have increased about 25% in the last 20 years. The estimated cost of treating asthma in the U.S. exceeds $6 billion. About 25% of patients with asthma who seek emergency care require hospitalization. The largest single direct medical expenditure for asthma has been in patient hospital services (emergency care), at a cost of greater than $1.6 billion. The cost for prescription medications is at least $1.1 billion.
According to the National Ambulatory Medical Care Survey, asthma accounts for 1% of all ambulatory care visits and the disease continues to be a significant cause of missed school days in children. Despite improved understanding of the disease process and better drugs, asthma morbidity and mortality continues to rise in this country and worldwide. Thus, asthma constitutes a significant public health problem.
The pathophysiologic processes that attend the onset of an asthmatic episode can be broken down into essentially two phases, both marked by bronchioconstriction, that causes wheezing, chest tightness, and dyspnea. The first, early phase asthmatic response is triggered by allergens and irritants. Allergens cross-link immunoglobulin (IgE) molecules bound to receptors on mast cells and basophils, causing them to release a number of pre-formed inflammatory mediators, including histamine. Additional triggers include the osmotic changes in airway tissues following exercise and/or the inhalation of cold, dry air. The second, late phase response that follows is characterized by infiltration of activated eosinophilis and other inflammatory cells into airway tissues, epithelial desquamation and by the presence of highly viscous mucus within the airway. The damage caused by this inflammatory response leaves the airways “primed” or sensitized, such that smaller triggers are required to elicit subsequent asthma symptoms.
For instance, human allergic asthma, a disease characterized by airway hyperresponsiveness and bronchial inflammation, is mediated by a variety of activated leukocytes, including eosinophils, mast cells, CD4+ T lymphocytes, and CD19+ B cells.
Current treatments, which improve airway hyperresponsivenss, include various anti-inflammatory agents, which reduce mucosal inflammation and asthma pathogenesis; however their efficacies vary markedly.
Short acting β2-adrenegric agonists, terbutaline and albuterol, long the mainstay of asthma treatment, act primarily during the early phase as bronchodilators. The newer long acting β2 agonists do not possess significant anti-inflammatory activity; they have no effect on bronchial hyperreactivity.
Numerous other drugs target specific aspects of the early or late asthmatic responses. For example, antihistamines, like loratadine, inhibit early histamine-mediated inflammatory responses. Other antihistamines, such as azelastine and ketotifen, have both anti-inflammatory and weak bronchodilatory effects, but they currently do not have any established efficacy in asthma treatment.
Phosphodiesterase inhibitors, like theophylline/xanthines, may attenuate late inflammatory responses, but there is no evidence that the compounds decrease bronchial hyperreactivity. Anticholinergics, like ipratopium bromide, which are used in cases of acute asthma to inhibit severe bronchoconstruction, have no effect on early or late phase inflammation, no effect on bronchial hyperreactivity and therefore essentially have no role in chronic therapy.
The corticosteroid drugs, like budesonide, are among the most potent anti-inflammatory agents. Inflammatory mediators or release inhibitors, like cromolyn and nedocromil, act by stabilizing mast cells and inhibiting the late phase inflammatory response to allergen. Thus, cromolyn and nedocromil, as well as the corticosteroids, all reduce bronchial hyperactivity by minimizing the sensitivity effect of inflammatory damage to the airways. These anti-inflammatory agents, however, do not produce bronchodilation.
Thus, while numerous drugs are currently available for the treatment of asthma, these compounds are primarily palliative and/or have significant side effects.
Unfortunately, none of the aforementioned drugs target the underlying cause of asthma.
Consequently, new therapeutic approaches which target the underlying cause rather than the cascade of symptoms would be highly desirable. The present inventors have searched for the underlying cause of asthmas, especially human allergic asthma. In asthma, CD4+ T cells secrete IL-4, a (Th-)2 type cytokine, which is required for IgE production and which is implicated in airway hyperresponsiveness, as well other cyctokines which increase IgE production.
The present inventors have found that a tetracycline congener, minocycline or doxycycline suppress human and murine IgE production. More specifically, it has been found that minocycline and doxycycline lower IgE concentrations. Further, it has been found that minocycline suppresses human and murine IgE production in vivo and that minocycline and another tetracycline congener, doxycycline, suppresses human IgE production in vitro.
It has been reported that allergic steroid dependent asthmatic patients treated with an oral administration of minocycline improved their symptoms (A.M. and P.M.), and decreased oral corticosteroid requirements See, Joks, et al., J. Allergy Clin. Immunol. 1998, 101:562. Additional studies of O'Dell, et al. in Arthritis Rheum: 1997, 40: 842-848 and Arthritis Rheum: 1999, 42:1691-1695 have shown that treatment of mild and moderate rheumatoid arthritis (RA) patients with minocycline had no side effects, and appears to be an effective therapy for early RA. Moreover, Yu, et al. in Arthritis Rheum: 1992, 35: 1150-1155 reported that treatment of dogs with minocycline or doxycycline reduced the severity of osteoarthritis (OA), while studies by Thong, et al. in Clin Exp Immunol., 1979, 35:443-446, have shown that doxycycline and tetracycline inhibit the ability of mice to mount delayed-type hypersensitivity responses. Further, studies in vitro have demonstrated that treatment of human whole blood cultures with minocycline or tetracycline at physiological doses inhibits mitotic responses to phytohemagglutinin (See Ingham, et al., Antimicrob Chemother, 1991, 27: 607-617) and inhibits inducible nitric oxide synthase (iNOS) expression by murine macrophages See Amin, et al., PNAS, 1996, 93: 14014-14019. In addition, it has been found that both minocycline and doxycycline suppress anti-CD40 rhIL-4 mediated in vitro induction of IgE responses by patient PBMC (peripheral blood mononuclear cells) in a dose dependent manner. (Smith-Norowitz, et al. Annals of Allergy, Asthma & Immunology, 2002, 89:8, 172-179. In addition, it has been shown that doxycycline suppresses PHA/IL-4 mediated IgE response by normal mouse spleen cells. Kuzin, et al. International Immunol 12, 921-931 (2000).
Although minocycline and doxycycline show effectiveness in suppressing excess IgE levels, being tetracyclines, they have the same adverse effects associated with tetracyclines. For example, a high percentage of patients are unable to tolerate oral tetracyclines for extended periods. The intolerance to tetracyclines can manifest itself into gastrointestinal problems, e.g., epigastric pain, nausea, vomiting and diarrhea or other problems related to taking the tetracyclines for long term treatment, such as mucosal candidiasis, staining teeth and the like.
The objective of the present invention is to find molecules that suppress IgE products, and reduce and/or eliminate the aforementioned side effects associated with tetracyclines. The present invention is directed to a means of achieving this objective by making modifications of the structures of the minocycline and doxycycline. More specifically, the present invention is directed to these new molecules and their use in suppressing excess IgE levels in patients suffering from asthma, allergies, inflammatory conditions, or other diseases where IgE is pathogenic.